The goal of the present proposal is to gain insight into the mechanisms governing homeostatic neuronal plasticity caused by lasting changes in the GAB Aergic inhibition of central neurons. The equilibrium between excitation (E) and inhibition (I) in the CNS (the E/I balance) is widely accepted to depend on the fine-tuning of its individual components, thus preventing it from tipping over. The overall hypothesis of this proposal can be summarized as follows: changes specifically affecting one of the two types of GABAergic inhibition (phasic/synaptic and tonic/extrasynaptic) will result in well-defined homeostatic changes in the other type of inhibition and in the intrinsic and synaptic excitation of neurons. The end result will be an overall change in excitability capable of balancing out the offset inhibition. Distinct changes in the two functionally separate types of inhibition are expected to differentially offset the E/I balance resulting in markedly different compensatory inhibitory and excitatory alterations. Experimentally, the two types of inhibition will be independently altered by pharmacological, molecular biological or genetic means. The resulting offset in the E/I balance will be studied using high resolution electrophysiological recordings in long-term organotypic slice cultures and acute brain slices obtained from mice. Other experimental approaches will include collaborative anatomical, immunocytochemical, pharmacological, and molecular biological techniques. Homeostatic alterations in the E/I balance will be addressed in a highly specific manner using appropriate knockin and knockout mice for specific GABAA receptor (GABAAR) subunits and second messenger systems. The proposed studies will further our understanding of the physiological plasticity in the CNS, and will help form the basis for therapeutical advances rationally aimed at preventing pathological plasticity of GABAARs. Awareness of the excitatory inertia following withdrawal from allosteric GABAAR modulators, knowledge about the site of action and plasticity of neurosteroids, BZ and alcohol, and a fundamental understanding of homeostatic inhibitory plasticity will advance drug discovery for the treatment of many severely incapacitating neurological and psychiatric disorders with known involvement of the GABA system. Our findings could provide the basis for novel and rationally targeted therapeutical approaches for the cure of anxiety, stress, benzodiazepine withdrawal, and epilepsy.